Novel Treatment Strategies
in IgE-Mediated Allergy

Cytokines and Cytokine Receptor-Antagonists

Hans-Uwe SimonChairman and Professor of Pharmacology
Department of Pharmacology
University of Berne
Berne, Switzerland

Extensive characterization of the immunopathogenesis of IgE-mediated
allergic disorders suggests that Th2 cytokines (IL-4, IL-5, IL-9,
IL-13) play central roles in the inflammatory process by regulating
the production of IgE, the effector functions of mast cells and
eosinophils, and by promoting transendothelial cell migration.
In contrast, IFN-,
a so-called Th1 cytokine, has the capacity of suppressing IgE
synthesis. Defective IFN-
expression has often been associated with atopy and IgE-mediated
allergies. The dysbalance in the expression of Th1 and Th2 cytokines
might largely be responsible for the initiation and maintenance
of the allergic inflammatory process in diseases such as bronchial
asthma (1) or atopic dermatitis (2). The increasing knowledge
in this area has provided the basis for a number of novel therapies.

One approach is simply adding cytokines, which are not sufficiently
expressed, or neutralizing cytokines, which are largely produced.
Other approaches to decrease cytokine levels include the blockade
of signalling molecules, the inhibition of transcription factors,
or decreasing the levels of specific mRNA. In this presentation,
I concentrate on the first approach.

IL-12 is produced by antigen-presenting cells and drives Th1
differentiation. On the other hand, it blocks Th2 differentiation,
mainly by increasing the production of IFN-.
Although experiments in animal models of allergic inflammation
were encouraging, clinical trials with IL-12 or IFN-
were often disappointing. It is possible that local rather than
systemic therapy is more efficient and less toxic. Some patients
with severe corticosteroid-resistant asthma may benefit from systemic
low-dose IFN-
treatment (3).

The neutralization of proinflammatory cytokines is another simple
approach for an anti-inflammatory therapy. A soluble IL-4 receptor
antagonist has been developed and successfully used in moderate
asthma (4). The neutralization of IL-13 in mice prevented airway
hyperreactivity and mucus secretion (5). Soluble IL-13 receptor
antagonists are currently under development for human trials.
Neutralization of IL-5 by using a humanized monoclonal antibody
to IL-5 reduced blood eosinophils and prevented eosinophil recruitment
into the airways (6). Although the clinical efficacy of this drug
appreared to be disappointing in mild asthma, further studies
are required to evaluate its role in the treatment of eosinophilic
disorders.

In conclusion, cytokines are targets of novel antiallergic drugs.
The evaluation of such agents is at a preliminary stage. Some
of the newly developed drugs might either be alone or in combination
useful in the treatment of IgE-mediated allergies.